DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application/Claims
The preliminary amendment, filed 01/11/2024, is acknowledged. Claims 3-4, 7-10, 14-18, 23-24, 26, 28, 30-60, 62, 64-72, 74-103, 105-120, 122-128, and 130-132 are canceled. Claims 1-2, 5-6, 11-13, 19, 21-22, 25, 27, 29, 61, 63, 73, 104, 121, and 129 are currently amended. Claims 1-2, 5-6, 11-13, 19-22, 25, 27, 29, 61, 63, 73, 104, 121, and 129 are currently pending and are examined on the merits herein.
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2021/060073, filing date 11/19/2021, which claims the benefit of the prior-filed United States Provisional Patent Application Nos. 63/115,824 (filing date 11/19/2020) and 63/115,833 (filing date 11/19/2020).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/26/2023 has been fully considered by the examiner.
Specification
The use of the terms Orbitrap, Mascot, Thermo Fisher, Invitrogen, and Corning, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 101
Claims 1-2, 5-6, 11-13, 19-22, 25, and 129 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon judicial exception without significantly more. The claims are drawn to naturally occurring peptides. The judicial exception is not integrated into practical application because the claims read on natural phenomena. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The claims are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106.III.
Step 1: Is the claim drawn to a process, machine, manufacture or composition of matter?
Yes. The claims are drawn to a composition of matter (claims 1-2, 5-6, 11-13, 19-22, 25, and 129) which is one of the four statutory categories. Claim 1 recites an isolated peptide. Claims 2, 5-6, 11-13, 19-22, 25, and 129 are dependent on claim 1.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes.
With respect to claims 1-2, 5-6, 11-13, 19-22, 25, and 129, instant SEQ ID NOS: 1-2, 163, 179, and 221 (from recited “Table 1” of claim 1) represent amino acid peptide fragments from the following full-length naturally occurring proteins:
SEQ ID NO: 1[Wingdings font/0xE0]Human PBK; see Uniprot.org, Q96KB5, PBK_Human, residues 288-297, p.8, 12/06/2005.
SEQ ID NO: 2[Wingdings font/0xE0]Human KIF2C; see Uniprot.org, Q99661, KIF2C_Human, residues 404-412, p.8, 01/23/2002.
SEQ ID NO: 163[Wingdings font/0xE0]Human IGF2BP3; see Uniprot.org, O00425, IF2B3_Human, residues 552-560, p.7, 07/28/2009.
SEQ ID NO: 179[Wingdings font/0xE0]Human CDC6; see Uniprot.org, Q99741, CDC6_Human, residues 354-362, p.7, 05/01/1997.
SEQ ID NO: 221[Wingdings font/0xE0]Human ASPM; see Uniprot.org, Q8I2T6, ASPM_Human, residues 818-826, p.7, 11/25/08.
Claim 19 also recites a nucleic acid encoding the sequence(s) of claim 1. Therefore, the claims encompass naturally occurring phenomena.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into an application?
No.
Claim 1 recites the additional limitation that the isolated peptide comprises at least 85% sequence identity to a peptide of Table 1, but does not integrate the judicial exception into a practical application
Claim 2 recites the additional limitation that the peptide comprises at least 6 contiguous amino acids of a peptide of Table 1 and/or wherein the peptide consists of 9 amino acids, but does not integrate the judicial exception into a practical application.
Claim 5 recites the limitation that the peptide is immunogenic but does not integrate the judicial exception into an application.
Claim 6 recites the additional limitation that the peptide is modified and wherein the modification comprises conjugation to an antibody, a lipid, an adjuvant, or a detection moiety, but does not integrate the judicial exception into a practical application.
Claim 11 recites the limitation that the peptide comprises 100% sequence identity to a peptide of Table 1, but does not integrate the judicial exception into a practical application.
Claim 12 recites the additional limitation of a molecular complex or composition comprising the peptide of claim 1 and an MHC polypeptide, but does not integrate the judicial exception into a practical application.
Claim 13 recites a pharmaceutical composition comprising the isolated peptide of claim 1 and a pharmaceutical carrier, but does not integrate the judicial exception into a practical application.
Claim 19 recites the additional limitation of a nucleic acid that encodes the peptide of claim 1, but does not integrate the judicial exception into a practical application.
Claim 20 recites the additional limitation of an expression vector that comprises the nucleic acid of claim 19 that encodes the peptide, but does not integrate the judicial exception into a practical application.
Claim 21 recites the additional limitation of a host cell that comprises the nucleic acid of claim 19, but does not integrate the judicial exception into a practical application.
Claim 22 recites the additional limitation of an in vitro isolated dendritic cell comprising the peptide of claim 1, but does not integrate the judicial exception into a practical application.
Claim 25 recites the additional limitation of a peptide-specific binding molecule that specifically binds to a peptide of claim 1, but does not integrate the judicial exception into a practical application.
Claim 129 recites the additional limitation of a kit comprising the peptide of claim 1 in a container, but does not integrate the judicial exception into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No.
Regarding claims 1-2 and 11, there are no additional recited elements that amount to significantly more than what is found in the naturally occurring peptide.
Regarding claim 5, there are no additional recited elements that amount to significantly more than what is found in the naturally occurring peptide, as the limitation of “immunogenicity” is an inherent property of the naturally occurring peptide.
Regarding claims 6, 20-22, and 25, there are no additional recited elements that amount to significantly more, because conjugation to detection moieties, expression vectors, host cells, isolated dendritic cells, and peptide-specific binding molecules (e.g., antibodies), respectively, are routinely used in the art.
Regarding claims 12-13 and 129, there are no additional recited elements that amount to significantly more, because molecular compositions, pharmaceutical compositions, and kits, respectively, are intended uses of the peptide which are not additional elements of the peptide itself. Further, regarding claim 129, the additional recitation of a container does not amount to significantly more, because containers are routinely used in the art.
Regarding claim 19, there are no additional recited elements that amount to significantly more, as nucleic acids encoding the naturally occurring peptide also are natural phenomena.
Therefore, the claims encompass a naturally occurring phenomenon that is not markedly different in structure from a naturally occurring product.
Without any evidence to the contrary, the peptide functionality and structure
would not be markedly different from that of the naturally occurring CPNE4. Because
there is no difference in the characteristics (structural, functional, or otherwise) between
the claimed and naturally occurring proteins, the claimed invention does not have
markedly different characteristics from what exists in nature. See, e.g., MPEP 2106).
Accordingly, the claims are directed to a judicial exception. Because the claim
does not include any additional features that could add significantly more to the
exception, the claim does not qualify as eligible subject matter under 35 U.S.C §101.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 5-6, 11-13, 19-22, 25, 27, 29, 61, 63, 73, 104, 121, and 129 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-2, and 11 recite “a peptide of Table 1.” Claims 2, 5-6, 11-13, 19-22, 25, 27, 29, 61, 63, 73, 104, 121, and 129 are all dependent upon claim 1, and thus also include the “Table 1” reference limitation.
MPEP §2173.05(s) states the following: Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
Table 1 of the instant disclosure lists peptides associated with SEQ ID NOs: 1-243. Thus, a reference to peptides of SEQ ID NOs: 1-243 provides a practical way to define the invention in words. Thus, the claims are rejected under 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter.
Claim 121 is further rejected based on the recitation of its dependence on claim 113 which was previously canceled. For further examination, claim 121 is interpreted as dependent upon claim 12.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 63 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cancer, does not reasonably provide enablement for the prevention of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) The nature of the invention; (2) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claim 63 is drawn to a method of administering a peptide for use in preventing cancer.
The breadth of the claims
The claim is broad in that it encompasses the prevention of any cancer.
The claim is broad and inclusive of all types of cancer. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. For example, there are solid cancers of the brain, spine, live, prostate, testes, ovaries, bile duct, blood vessels, lung and pleural cavity, thyroid, skin (including melanoma), colon, prostate, kidneys, breasts, testicles, vulva and vagina, uterus, cervix, fallopian tubes, thymus, stomach, esophagus, spleen, salivary glands, heart, oral cavity, adrenal glands, eye, head and neck, bladder, bone, and gall bladder. Each of these types of cancer have potentially dozens of sub-categories that each have unique physiological and etiological characteristics.
The amount or direction provided by the inventor/ the existence of working examples
The instant disclosure does not provide a special definition for “prevention.” Thus “prevention” is interpreted based on Merriam-Webster. Dictionary: “Prevent/Prevention” (10/18/2019), Internet – Wayback Machine, p.1 (herein referred to as MWD) which defines prevention as “to keep from happening or existing” (p.1). The instant specification also does not provide any mention of “prevention” nor does the instant disclosure provide any examples or drawings supporting that prevention with the claimed agents or methods occurred.
The disclosure does not demonstrate the prevention of cancer. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method or product that could be used to determine that cancer was prevented using the claimed method as there is no disclosed method or product to determine that cancer would have predictably occurred without treatment.
The state of the prior art/ the level of predictability in the art
There are no art recognized methods that could be used to establish that the cancer was prevented using the claimed therapeutic method. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed cancer in order to determine that the cancer was prevented using the claimed methods.
Regarding biomarkers (and immunotherapies) in cancer, McKean et al. Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291 (herein referred to as McKean) teach that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (abstract). McKean also teach that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
Ahmadzada et al. An update on predictive biomarkers for treatment selection in non-small cell lung cancer. Journal of Clinical Medicine (2018), 7:153, p.1-12 (herein referred to as Ahmadzada) also suggest that it is still difficult to apply classification of cancers to select targeted therapies. For example, Ahmadzada teaches that non-small cell lung cancer is a highly heterogeneous disease that develops from genetic mutations and gene expression patterns that initiate uncontrolled cellular growth, proliferation, and progression (p.2). Ahmadzada also teaches that only 15-25% of non-small cell lung cancer patients benefit from immunotherapy, suggesting the need for novel biomarkers to identify the best candidates for treatments (p.7). Further, Ahhmadzada et al. also recognize that the heterogeneity of NSCLC remains a key barrier to accurate molecular classification and necessitates individualization of treatment (p.8)
The American Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention. 1/1/2025. Internet – Wayback Machine. p.1-4).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Studies regarding treatment and prevention of cancer are underway that aim to improve earlier detection and better treatments for cancer. However, based on the disclosure and the prior art, there is no known or disclosed method through which an ordinarily skilled artisan would have been able to predictably identify subjects who would have predictably developed cancer in order to determine that the cancer was prevented using the claimed methods. Therefore, in order to practice the invention as claimed, an ordinarily skilled artisan would have to participate in undue experimentation to determine a method that would allow for the prevention of cancer.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claim was determined to not meet the scope of enablement requirement of 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5, and 11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Fritsche, et al.—US20180125929A1.Novel immunotherapy against several tumors including gastrointestinal and gastric cancer. (publication date: 5/10/2018; effective filing date: 03/19/2010), herein referred to as Fritsche.
Fritsche teaches immunotherapies for cancer and compositions thereof; and, methods of treating various cancers (title; abstract). Fritsche teaches peptides, nucleic acids, and cells for use in immunotherapeutic methods (p.1, [0003]). Fritsche teaches peptides, and nucleic acids encoding the peptides, that are useful for generating an immune response in a patient by which tumor cells can be destroyed (p.7, [0074]). Fritsche specifically teaches peptides of SEQ ID NO: 50 (i.e., instant SEQ ID NO: 1 of SYQKVIELF), SEQ ID NO: 33 (i.e., instant SEQ ID NO: 2 of IYNGKLFDLL), SEQ ID NO: 63 (i.e., instant SEQ ID NO: 163 of KIQEILTQV), SEQ ID NO: 76 (i.e., instant SEQ ID NO: 179 of ILQDRLNQV), and SEQ ID NO: 2 (i.e., instant SEQ ID NO: 221 of SYNPLWLRI), which are amino acid sequences from PBK (PDZ-Binding Kinase) protein, KIF2C (Kinesin-Like Protein), IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3), CDC6 (cell division cycle 6 homolog), and ASPM (abnormal spindle-like microcephaly associated protein), respectively, which share 100% identity with each of instant SEQ ID NOs: 1 2, 163, 179, and 221, respectively (from instant Table 1; see Fritsche p.9, [0089]; p.10, [0096]); p.17, [0153]; p.18, [0164]; p.19, [0175]; Fritsche p.8, Table 2). Thus, Fritsche teaches that the peptides of SEQ ID NOs: 50, 33, 63, 76, and 2 comprise at least 6 contiguous amino acids. Further, SEQ ID NOs: 50, 33, 63, 76, and 2 each consist of 9 amino acids. Regarding the instant claim 5 recited limitation “ …wherein the peptide is immunogenic,” this describes an inherent property of the known naturally occurring sequences, taught by Fritsche, that does not render the claim patentably new (see MPEP §2112). The instant SEQ ID NOs: 1-2, 163, 179, and 221 necessarily possess the same property as Fritsche SEQ ID NOs: 50, 33, 63, 76, and 2, respectively, which possess the property of being immunogenic as evidenced by the instant disclosure (p. 11, [0038] and Table 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6, 12-13, 19-22, 25, 27, 29, 61, 63, 104, and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Fritsche, as applied to claim 1 above.
Fritsche teaches peptides comprising instant SEQ ID NOs: 1, 2, 163, 179, and 221 (instant claim 1).
Fritsche does not explicitly teach that any of the peptides taught by Fritsche SEQ ID NOs of claim 1 (described above) are modified via conjugation to a detection moiety (instant claim 6); a molecular complex or composition comprising the peptide of instant claim 1 (instant claim 12); a pharmaceutical composition comprising the isolated peptide and a pharmaceutical carrier (instant claim 13); a nucleic acid specifically encoding for the peptide of claim 1 (instant claim 19); an expression vector comprising the nucleic acid of the peptide (instant claim 20); a host cell comprising the nucleic acid (instant claim 21); an in vitro isolated dendritic cell comprising the peptide of claim 1 (instant claim 22); a peptide-specific binding molecule that binds to a peptide of claim 1 (instant claim 25); a method of making a cell by transferring the nucleic acid into the cell (instant claim 27); a method of producing cancer-specific immune effector cells (instant claim 29); a peptide-specific engineered T cell produced by the method of claim 29 (instant claim 61); a method of treating cancer in a subject or stimulating an immune response by administering the peptide of claim 1 (instant claim 63); a method of prognosing a patient or for detecting T cell responses in a patient by contacting a biological sample from the patient with the peptide of claim 1 (instant claim 104); or, a kit comprising the peptide of claim 1 in a container (instant claim 129).
Fritsche additionally teaches expression vectors capable of expressing nucleic acids encoding the peptides and host cells comprising the nucleic acid; and that the host cell is an antigen presenting cell that is a dendritic cell (p.21, [[0198], [0200] – [0202]). Fritsche teaches that the dendritic cells are useful in expressing the peptides because they may then be loaded into appropriate MHC molecules (p.34, [0308]). Fritsche teaches that DNA is transformed into host cells (i.e., transferring the nucleic acid into a cell/dendritic cell) and cultured to permit expression of peptides which can then be recovered (p.33, [0301]). Fritsche teaches sequences, constructs, vectors, and clones in enriched and isolated forms (p.4, [0047]). Fritsche teaches methods comprising administering compositions to patients wherein the composition contains a population of activated T cells that selectively recognize cells in the patient that aberrantly express peptide, and that bind to the peptide in a complex with an MHC class I molecule (abstract). Fritsche teaches that the peptide compositions contain a pharmaceutically acceptable carrier (abstract); and, that the peptides of the pharmaceutical compositions comprise the peptides in either free form or in the form of a pharmaceutically acceptable salt (p.7, [0075]). Fritsche teaches novel peptide sequences and their variants derived from HLA class I molecules of cancer cells that can also be used in vaccine compositions for eliciting anti-tumor immune responses (i.e., immunogenic; p.1, [0003]). Fritsche additionally teaches a kit comprising the pharmaceutical compositions that comprise the peptide, in a container in solution or in lyophilized form (p.37, [0341]). Fritsche teaches a method of producing the peptide by culturing the host cell and isolating the peptide from the host cell or its culture medium (p21, [0203]). Fritsche teaches priming of T cells via isolation of T cells from leukapheresis products (p.39, [0363]). Fritsche teaches an in vitro method for producing activated cytotoxic T cells (CTLs), wherein the method comprises contacting in vitro CTLs with the antigen peptide loaded human MHC class I or II molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate the T cell in an antigen specific manner (p.21, [0204]; p.34, [0312]). Thus, Fritsche teaches a method of producing cancer/peptide-specific immune effector cells by obtaining a starting population of immune effector cells and contacting the cell population with the peptide to generate the peptide-specific immune effector cell.
Additional teachings by Fritsche further teaches that the peptides can be comprised in fusion proteins, and in particular fusion proteins that also comprise N-terminal amino acids of the HLA-DR antigen-associated invariant chain (p.21, [0195]). Fritsche teaches that the peptide can be conjugated to a suitable carrier such as keyhole limpet haemocyanin (KLH) or mannan; be tagged; be a fusion protein; or, be a hybrid molecule (p.35,k [[0329]). Fritsche teaches that the peptide can be tagged at the N-terminus or C-terminus with tags (such as FLAG, 3xFLAG, c-myc, or MAT) for purposes of detection, purification, and analysis (p.33, [0303; p.35, [0329]). Fritsch also teaches the concept of generating an MHC:peptide complex that can be pre-formed in order to generate artificial antigen presenting cells (aAPCs) that can be used to prime T cells; and, teaches that this system provides the benefit of controlling the density on aAPCs which allows for selectively eliciting high- or low-avidity antigen-specific T cell responses with high efficiency from blood samples (p.35, [0318]). Thus, Fritsche also teaches a peptide-specific MHC molecule. Fritsche additionally teaches that the peptides might be used to analyze lymphocyte responses against the peptides such as T cell responses or antibody responses against the peptide or the peptide complexed to MHC molecules (p.7, [0080]). Fritsche further teaches that these lymphocyte responses can be used as prognostic markers for decision on further therapy steps, surrogate markers in immunotherapy approaches aiming to induce lymphocyte responses by different means (e.g., vaccination of protein, nucleic acids, autologous materials, adoptive transfer of lymphocytes, or can be considered in the assessment of side effects for gene therapy. Additionally, Fritsche further teaches that the monitoring of such lymphocyte responses might also be a valuable tool for follow-up examinations of transplantation therapies (e.g., for the detection of graft versus host and host versus graft diseases (p.7, [0080]).
Regarding instant claim 6, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche by modifying the peptide taught by Fritsche to be conjugated to a tag, to arrive at the instantly claimed invention, in order to receive the expected benefit of serving as a detection tag that could also be used for purification and analysis (also taught by Fritsche). One of ordinary skill in the art would have a reasonable expectation of success because Fritsche teaches several tags that can be conjugated to the N- or C-terminus of the peptide.
Regarding instant claims 12 and 25, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche by modifying the peptide taught by Fritsche by complexing it with an MHC molecule to form a molecular MHC:peptide complex (also taught by Fritsche), in order to arrive at the instantly claimed invention, in order to receive the expected benefit that the complex can be used to generate aAPCs with controlled density and efficient T cell activation in patient samples. One of ordinary skill in the art would have a reasonable expectation of success because the combination of Fritsche prior art teachings results in a predictable result.
Regarding instant claims 13, 63, and 129: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche by using the peptide in a kit (also taught by Fritsche), to arrive at the instantly claimed invention, because the combination of prior art elements results in a predictable result of producing a kit that contains a pharmaceutical composition that comprises the peptide; and, one would be motivated to do so because Fritsche teaches kits of formulations of pharmaceutical compositions comprising the peptides that are useful in the treatment of cancers. One of ordinary skill in the art would have a reasonable expectation of success because Fritsche teaches the amino acid sequences for the peptides and teaches contents of kits, including containers.
Regarding instant claims 19-22, 27, 29, and 61: It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche by using a nucleic acid encoding the peptide and to use an expression vector and a host cell that is a dendritic cell to express the peptide, in order to arrive at the instantly claimed invention, because the combination of prior art elements results in a predictable result of using this method of making/producing cancer-specific immune effector cells that are peptide-specific engineered T cells. One of ordinary skill in the art would have a reasonable expectation of success because Fritsche also teaches that priming of T cells is performed by isolating T cells from leukapheresis products (i.e., by obtaining a starting population of immune effector cells and contacting the cells with the peptide to generate peptide-specific immune effector cells).
Regarding instant claim 104, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche by using the peptide contacted with the T cells for T cell activation (taught by Fritsche) in a method of prognosing a patient and for detecting T cell responses (also taught by Fritsche), to arrive at the instantly claimed invention, in order to receive the expected benefit that such a prognosing method would aid in decisions regarding therapy, provide surrogate markers for immunotherapy approaches, and considered in the assessment of side effects related to gene therapy (also taught by Fritsche).
Claims 1, 12, 73, and 121 are rejected under 35 U.S.C. 103 as being unpatentable over Fritsche as applied to claim 1 above, and further in view of Dössinger, et al. MHC multimer-guided and cell culture-independent isolation of functional T cell receptors from single cells facilitates TCR identification for immunotherapy. PLOS ONE (2013), 8:4, p.1-12 (herein referred to as Dössinger).
The combination of teachings by Fritsche teaches peptides comprising instant SEQ ID NOs: 1 and 2; and, an MHC:peptide complex composition, as described in detail above for instant claims 1 and 12.
The combination of teachings by Fritsche does not teach a method of cloning a peptide-specific TCR (T cell receptor) wherein the method comprises obtaining a starting population of immune effector cells, contacting the cells with the peptide to generate peptide-specific cells, purifying the peptide-specific cells, and isolating a TCR sequence from the purified cells (instant claim 73); or, a method comprising contacting a composition comprising an MHC: peptide complex with a composition comprising T cells wherein the MHC or peptide is conjugated to a detection tag in order to detect T cells bound to the peptide and/or MHC (instant claim 121).
Regarding instant claim 121: While the combination of Fritsche teaches 1) conjugating the peptide to a detection tag, 2) forming an MHC:peptide complex, and 3) using the peptide for activating T cells to elicit T cell responses, Fritsche does not specifically teach the use of a tagged peptide to detect T cells bound to the peptide and/or MHC polypeptide. Additionally, while Fritsche teaches that T cells can be clonally expanded via stimulation with a peptide antigen (p.3, [0023]; p.60, claim 5) and that the T cells are obtained autologously from a patient (i.e., from a patient sample; p60, claim 1), Fritsche does not specifically teach that the T cells are purified or that the TCR sequence is isolated from the T cells.
Dössinger teaches MHC multimer-guided and cell culture-independent isolation of functional TCRs from single cells to facilitate TCR identification for immunotherapy (title). Dössinger teaches that adoptive therapy using T cells redirected to target tumor- or infection-associated antigens is a promising strategy that has curative potential and broad applicability (abstract). Dössinger uses direct isolation of paired full-length TCR sequences from non-expanded antigen-specific T cells; uses MHC multimer-labeled and single cell-sorted T cells (i.e., isolated, purified T cells) to identify TCRs with high efficiency and specificity for oncogenes (abstract); and, uses genetic re-expression of isolated TCRs to demonstrate their functionality and target specificity (abstract). Dössinger teaches that, because not all T cells are expandable under similar conditions, in vitro culture-based protocols limit access to restricted TCR repertoire compositions; and, that this limitation can be overcome by direct ex vivo single-cell sorting of antigen-specific T cells and subsequent TCR cloning from individual cells, without the need for any in vitro propagation (p.1, col.2, para.2). Dössinger teaches that although many epitope-specific T cell populations are extremely rare, they can be accurately detected through the combination of MHC multimer-based pre-enrichment and combinatorial MHC multimer staining technologies (p.1, col.2, para.3). Dössinger teaches pre-enrichment of MHC multimer-binding cells and subsequently labeled the antigen-enriched cell fraction with a different label (i.e., a fluorophore). Dössinger further teaches detailed methods for TCR sequencing (p.2, col.1, para.1).
Regarding instant claim 73, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche with the teachings of Dössinger by using the peptide or peptide-MHC complex (taught by Fritsche) in a method of cloning peptide-specific TCRs by obtaining a population of T cells from a sample (taught by Fritsche), contacting the T cells with the peptide or peptide-MHC complex (taught by Fritsche and Dössinger), then purifying the T cells and isolating the TCR sequence from the cells (taught by Dössinger), to arrive at the instantly claimed invention, in order to receive the expected benefit of accurate detection and cloning of rare TCR-containing cells that are difficult to expand using in vitro-based propagation. One of ordinary skill in the art would have a reasonable expectation of success because both Fritsche and Dössinger teach contacting T cells with MHC-containing molecules for the purpose of expanding antigen-specific T cells for treatment of cancer.
Regarding instant claim 121, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Fritsche with the teachings of Dössinger by modifying the MHC label-based detection (taught by Dössinger) to use the detection moiety-labeled peptide (taught by Fritsche) or a detection moiety-labeled MHC:peptide complex (taught by the combination of Fritsche’s teachings), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of using a labeling technique to identify antigen-specific T cells, and thus TCRs. One of ordinary skill in the art would have a reasonable expectation of success because Fritsche teaches labeling of peptides and/or MHC:peptides and Dössinger teaches labeling of MHC multimers to bind antigen-specific T cells and Dössinger teaches specific protocols for TCR identification and sequencing for expansion of antigen-specific T cells for cancer treatment.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Copending Application 18/556,054
Claims 1-2, 5-6, 11-13, 19-22, 25, 27, 29, 61, 63, 73, 104, 121, and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 18, 20-21, 24, 27, 29, 64-65, 101, 103, 121, 146, 154, 156, 169, 203, 208, 225, and 233 of copending Application No. 18/556,054 (herein referred to as App’054); and, in further in view of Fritsche.
App’054 teaches a peptide comprising at least 70% sequence identity to a peptide of SEQ ID NOs: 1 (i.e., IYNGKLFDL), which is the same as instant SEQ ID NOs: 2 (App’054 claim 1; instant claims 1-2, 5). App’054 teaches a nucleic acid or expression vector encoding the peptide (App’054 claim 18; instant claims 19-20); a host cell comprising the nucleic acid or expression vector (App’054 claim 20; instant claim 21); an in vitro isolated dendritic cell comprising the peptide (App’054 claim 21; instant claim 22); a peptide-specific binding molecule that specifically binds to the peptide (App’054 claim 24; instant claim 25); a method of making a cell comprising transferring the nucleic acid or expression vector into the cell (App’054 claim 27; instant claim 27); a method of producing cancer-specific immune effector cells comprising obtaining a starting population of immune effector cells and contacting the starting population of immune effector cells with the peptide, thereby generating peptide-specific immune cells (App’054 claim 29; instant claim 29); a peptide-specific engineered T cell (App’054 claim 64; instant claim 61); a method of cloning a peptide-specific TCR comprising obtaining a starting population of immune effector cells, contacting the cells with the peptide, purifying the cells, and isolating a TCR sequence from the purified cells (App’054 claim 169; instant claim 73); a method for prognosing a patient or for detecting T cell responses in a patient comprising contacting a biological sample from the patient with the peptide (App’054 claim 208; instant claim 104); a method comprising contacting a composition comprising at least one MHC polypeptide and the peptide with a composition of T cells and detecting T cells with bound peptide and/or MHC polypeptide by detecting a detection tag conjugated to the peptide (App’054 claim 225; instant claims 6 and 121); and a kit comprising the peptide in a container (App’054 claim 233; instant claim 129).
App’054 does not teach a peptide that is at least 85% of instant SEQ ID NOs: 1 or 2 (instant claim 1); a peptide that is 100% identical to SEQ ID NOs: 1 or 2 (instant claim 11); a peptide that comprises at least 6 contiguous amino acids of a peptide of instant Table 1 and/or wherein the peptide consists of 9 amino acids (instant claim 2); that the peptide is immunogenic (instant claim 5); a molecular complex or composition comprising the peptide and an MHC polypeptide (instant claim 12); a pharmaceutical composition comprising the peptide and a carrier (instant claim 13); or, a method of treating cancer comprising administering the peptide (instant claim 63).
Fritsche teaches peptide SEQ ID NO: 33 which is identical to App’p54 SEQ ID NO: 1 and instant SEQ ID NOs: 2, as described in detail above (i.e., at least 85% identity); thus, Fritsche also teaches peptides that comprise at least 6 contiguous amino acids of a peptide from instant Table 1 and wherein the peptide consists of 9 amino acids. Fritsche teaches immunotherapies for cancer and compositions thereof; and, methods of treating various cancers (title; abstract). Fritsche teaches peptides, nucleic acids, and cells for use in immunotherapeutic methods (p.1, [0003]). Fritsche teaches peptides, and nucleic acids encoding the peptides, that are useful for generating an immune response in a patient by which tumor cells can be destroyed (p.7, [0074]). Fritsche further teaches expression vectors capable of expressing nucleic acids encoding the peptides and host cells comprising the nucleic acid; and that the host cell is an antigen presenting cell that is a dendritic cell (p.21, [[0198], [0200] – [0202]). Fritsche teaches that the dendritic cells are useful in expressing the peptides because they may then be loaded into appropriate MHC molecules (p.34, [0308]). Fritsche teaches that DNA is transformed into host cells (i.e., transferring the nucleic acid into a cell/dendritic cell) and cultured to permit expression of peptides which can then be recovered (p.33, [0301]). Fritsche teaches sequences, constructs, vectors, and clones in enriched and isolated forms (p.4, [0047]). Fritsche teaches methods comprising administering compositions to patients wherein the composition contains a population of activated T cells that selectively recognize cells in the patient that aberrantly express peptide, and that bind to the peptide in a complex with an MHC class I molecule (abstract). Fritsche teaches that the peptide compositions contain a pharmaceutically acceptable carrier (abstract); and, that the peptides of the pharmaceutical compositions comprise the peptides in either free form or in the form of a pharmaceutically acceptable salt (p.7, [0075]). Fritsche teaches novel peptide sequences and their variants derived from HLA class I molecules of cancer cells that can also be used in vaccine compositions for eliciting anti-tumor immune responses (i.e., immunogenic; p.1, [0003]). Fritsche additionally teaches a kit comprising the pharmaceutical compositions that comprise the peptide, in a container in solution or in lyophilized form (p.37, [0341]). Fritsche teaches a method of producing the peptide by culturing the host cell and isolating the peptide from the host cell or its culture medium (p21, [0203]). Fritsche teaches priming of T cells via isolation of T cells from leukapheresis products (p.39, [0363]). Fritsche teaches an in vitro method for producing activated cytotoxic T cells (CTLs), wherein the method comprises contacting in vitro CTLs with the antigen peptide loaded human MHC class I or II molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate the T cell in an antigen specific manner (p.21, [0204]; p.34, [0312]). Thus, Fritsche teaches a method of producing cancer/peptide-specific immune effector cells by obtaining a starting population of immune effector cells and contacting the cell population with the peptide to generate the peptide-specific immune effector cell.
Additional teachings by Fritsche further teaches that the peptides can be comprised in fusion proteins, and in particular fusion proteins that also comprise N-terminal amino acids of the HLA-DR antigen-associated invariant chain (p.21, [0195]). Fritsche teaches that the peptide can be conjugated to a suitable carrier such as keyhole limpet haemocyanin (KLH) or mannan; be tagged; be a fusion protein; or, be a hybrid molecule (p.35,k [[0329]). Fritsche teaches that the peptide can be tagged at the N-terminus or C-terminus with tags (such as FLAG, 3xFLAG, c-myc, or MAT) for purposes of detection, purification, and analysis (p.33, [0303; p.35, [0329]). Fritsch also teaches the concept of generating an MHC:peptide complex that can be pre-formed in order to generate artificial antigen presenting cells (aAPCs) that can be used to prime T cells; and, teaches that this system provides the benefit of controlling the density on aAPCs which allows for selectively eliciting high- or low-avidity antigen-specific T cell responses with high efficiency from blood samples (p.35, [0318]). Thus, Fritsche also teaches a peptide-specific MHC molecule. Fritsche additionally teaches that the peptides might be used to analyze lymphocyte responses against the peptides such as T cell responses or antibody responses against the peptide or the peptide complexed to MHC molecules (p.7, [0080]). Fritsche further teaches that these lymphocyte responses can be used as prognostic markers for decision on further therapy steps, surrogate markers in immunotherapy approaches aiming to induce lymphocyte responses by different means (e.g., vaccination of protein, nucleic acids, autologous materials, adoptive transfer of lymphocytes, or can be considered in the assessment of side effects for gene therapy. Additionally, Fritsche further teaches that the monitoring of such lymphocyte responses might also be a valuable tool for follow-up examinations of transplantation therapies (e.g., for the detection of graft versus host and host versus graft diseases (p.7, [0080]).
Regarding instant claims 1-2, 13, and 63, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’054 with the teachings of Fritsche by modifying the peptide taught by App’054 to have greater sequence identity by using Fritsche’s SEQ ID NO: 33 and to use a peptide in a kit (also taught by Fritsche), to arrive at the instantly claimed invention, because the combination of prior art elements results in a predictable result of producing a kit that contains a pharmaceutical composition comprising the peptide and a carrier (taught by Fritsche). One of ordinary skill in the art would have been motivated to do so and would have a reasonable expectation of success because Fritsche teaches that the peptide (taught by App’054 and Fritsche) can be used in kits formulated for the treatment of cancer in a subject (taught by Fritsche). One would have a reasonable expectation of success because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would also have a reasonable expectation of success because the peptides are based on the same antigen sequence.
Regarding instant claims 12-13, it would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’054 with the teachings of Fritsche by complexing the peptide with an MHC molecule to form a molecular MHC:peptide complex (also taught by Fritsche), in order to arrive at the instantly claimed invention of using an immunogenic peptide to form a molecular complex with an MHC polypeptide (taught by Fritsche and App’054), in order to receive the expected benefit that the immunogenic MHC:peptide complex can be used for T cell activation in patient samples for cloning of antigen-specific T cells (taught by App’054). One of ordinary skill in the art would have a reasonable expectation of success because the combination of prior art teachings results in a predictable result of antigen-specific T cell activation (as taught by App’054 and Fritsche).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647